Bone loss during critical illness: a skeleton in the closet for the ICU survivor?
Authors
1. Dr. David M Griffith MBChB FRCA
Advanced Trainee and Research Fellow in Intensive Care Medicine
Edinburgh Royal Infirmary, Edinburgh
2. Professor Tim S Walsh BSc(Hons) MBChB(Hons) FRCP FRCA MD MRes(PHS)
Professor of Critical Care, Clinical and Surgical Sciences, Edinburgh University
Consultant in Anaesthetics and Intensive Care, Edinburgh Royal Infirmary, Edinburgh
Correspondance:
Professor Tim S Walsh
Critical Care Research Team
Room GU309
Chancellor’s Building
49 Little France Crescent
Edinburgh EH16 4SB
Medical subject headings:
Critical Care, Intensive Care, Bone and bones, Bone resorption, Osteoporosis, Survivors, Quality of Life
Bone loss during critical illness: a skeleton in the closet for the ICU survivor?
“I have no history but the length of my bones”
Robin Skelton
As more patients receive multiple organ support in critical care units, many of whom are elderly and/or have significant co-morbidities, attention is turning towards an ever increasing population of ICU survivors (1). Critical illness is recognised to result in a “post-ICU syndrome”, which can occur whatever the original presenting illness and result in cognitive, neurological and physical function impairments which significantly affect patients’ quality of life for many months or years (2). These impairments and disabilities also place a heavy burden on health care systems and carers (3). In recent years our knowledge of the prevalence of psychological and physical problems has improved through cohort studies, and research is beginning to explore the risk factors, mechanisms, and possible treatments that may affect the severity and duration of issues ranging from psychological conditions such as post-traumatic stress disorder to physical problems such as fatigue and breathlessness. Until now very little work has specifically investigated the affect of critical illness on the skeleton, having focussed mainly on neuromuscular dysfunction.
Osteoporosis is a major public health issue which has been estimated to affect 55% of Americans aged 50 and above, of whom 80% are women (4). It is responsible for millions of fractures annually, mostly involving the lumbar vertebrae, hip, and wrist. The World Health Organization defines osteoporosis as a bone mineral density (BMD) that is more than 2.5 standard deviations below the mean BMD of young adult women (5). The disease can be classified as primary type 1, primary type 2, or secondary. Primary type 1 or postmenopausal osteoporosis is the form most common in women after menopause, whereas Primary type 2 osteoporosis occurs after age 75 and is seen in both females and males at a ratio of 2:1. Secondary osteoporosis may arise at any age and affects men and women equally. This form of osteoporosis results from chronic predisposing medical problems or disease, or prolonged use of medications such as glucocorticoids.
A significant proportion of patients admitted to intensive care units will possess strong risk factors for osteoporosis, such as female gender, older age, a positive family history, low BMI, and Caucasian origin. Many will also be smokers, have a history of prior corticosteroid use, chronic inflammatory disease, or reduced mobility (6). Although no studies have formally quantified the prevalence of osteoporosis among patients admitted to critical care units it is likely that many suffer from this condition. Given the potential for osteoporosis-related fractures to impact on long term quality of life, together with the availability of potential treatments, it is relevant to understand whether an episode of critical illness increases its severity or rates of disease progression and complications.
In this issue of Critical Care Medicine, Dr Orford and colleagues address this issue. They are the first to examine fracture incidence in patients who survive critical illness. The authors estimated fracture incidence for both men and women cared for in a major Australian ICU who required greater than 48 hours of mechanical ventilation, and were able to compare the female cohort to age matched controls from a high quality prospective population based osteoporosis study from the same region (7). Fracture incidence was assessed in the cohort of patients discharged after critical illness by searching electronic radiology reports for a median follow up time of 3.7 years for females and 4.0 years for men. They found that 14% of female and 10% of male survivors who had been ventilated for more than 48 hours sustained fractures in the follow up period. In female survivors the overall incidence trended to a higher fracture rate over the follow up period than was present in the population controls, but this was not statistically significant (hazard ratio 1.20 95%CI 0.84-1.71, P=0.31). Interestingly, when older female patients (aged 60 or greater) were analysed as an age matched sub-group there was a statistically significant increase in fracture rate suggesting clinically important increases in fracture rates (hazard ratio 1.65 95%CI 1.08-2.52, P=0.02). As older women are more likely to have co-existing osteoporosis when they suffer their critical illness, and/or are more prone to developing it, this observation raises the possibility that critical illness itself may accelerate osteoporosis development and increase the chance of fracture.
The study was not prospective, such that fracture detection relied on patients having undergone imaging in the radiology departments included in the region. It is possible that fracture under-detection occurred in both critically ill and control populations, and ascertainment bias due to imbalance between the groups cannot be excluded. The excess of fractures in the female ICU survivors was attributable largely to vertebral fractures. These comprised a much higher proportion of the fractures in the ICU cohort (41.7%) than the population control cohort (17.4%) and could also be a form of ascertainment bias perhaps attributable to increased imaging in post ICU patients, for example chest radiography for respiratory symptoms. As pointed out by the authors, the retrospective design also makes it difficult to disentangle pre-existing risk factors from the effects of critical care, and confounding factors may not have been adequately controlled for. Despite these limitations the findings raise the possibility that critical illness increases the risk of subsequent osteoporotic fractures.
Bone turnover can be assessed in patients using various biochemical markers (8). These have been broadly categorised as collagenous bone resorption markers, osteoclast regulatory proteins, and bone formation markers. Peptide fragments from the breakdown of mature collagen are the most commonly used measures of bone resorption and include the pyridinolines (pyridoniline and deoxypyridinoline), which can be detected in the serum and the urine (8). Increased bone turnover in critically ill patients, particularly those who require multiple organ support for prolonged periods, has been reported in the literature for well over a decade (9) (10) (11). Shapses and colleagues compared bone turnover in a small sample of critically ill patients following gastrointestinal surgery, all of whom were receiving parenteral nutrition,to age-matched healthy volunteers. Excretion of pyridinium cross-links was increased in the critically ill sample when compared to healthy volunteers and was more pronounced in patients who had a longer ICU stay (9). Smith et al reported increased bone resorption compared to healthy controls in 23 patients with sepsis and trauma measured using pyridinoline/creatinine (PYD/Cr) and deoxypyridinoline/creatinine (DPD/Cr) ratios. The authors found this was particularly pronounced in the subgroup of septic patients who had a 10-fold increase in PYD/Cr ratio and a 6-fold increase in DPD/Cr ratio (10). Serum markers of osteoblast activity were increased at ICU admission in Van Den Berghe’s study of vitamin D in critically ill patients compared to healthy controls. This was accompanied by a similar increase in urinary DPD and PYD implying upregulation of both osteoclast and osteoblast activity but with an imbalance in favour of bone resorption (11). These studies all suggest that critical illness is associated with changes to normal bone metabolism, which most likely favour bone breakdown and deminerlaisation.
Although the impact of critical illness on bone mineralisation is ill defined, much can be inferred from other settings and the known pathophysiological processes that occur. Factors known to cause bone loss are summarised in table 1, and have been recently reviewed by Via and colleagues (12). The multiple potential mechanisms whereby critical illness could result in excessive osteoclast activity, bone loss and demineralisation provide a strong biological plausibility for increased risk of subsequent osteoporosis, especially following prolonged critical illness.
Table 1: Potential risk factors for bone loss during critical illness (12)
Risk factor / MechanismImmobility (13) (14) / Increased calcium resorption inhibits PTH and 1,25 dihydroxy vitamin D (1,25-D) formation
Inflammatory Cytokines (12) / Stimulate osteoclast formation and differentiation
Stimulate mature osteoclasts
Inhibit osteoblast formation
Endocrine dysfunction (12) / Increased cortisol
Depressed GH and IGF-1
Decreased TSH and T4
Vitamin D deficiency (11) / Disturbance in calcium homeostasis
Glucocorticoids (15) / Decrease in osteoblastic activity
Although the study by Orford and colleagues requires validation in prospective adequately controlled studies with a low risk of bias, their findings are particularly interesting because potential therapies exist to prevent or minimise the detrimental effects of critical illness on bone metabolism. These include vitamin D and biphosphonate therapy. Biphosphonates in particular are well-established effective treatments for osteoporosis, bone metastases, and other bone diseases. They act by promoting osteoclast apoptosis thereby reducing bone loss. Some small studies have used both vitamin D and biphosphonates in critically ill patients, and demonstrated biochemical evidence of reduced bone resorption(11), (16). The overall excellent safety profile of biphosphonates make them a potentially attractive therapeutic option for the chronically critically ill, although caution is required in patients with renal failure and they have also been associated with fever and atrial fibrillation both of which could have adverse effects in frail patients.
Orford et al have opened a new avenue of research into the consequences of critical illness. Their data support the need for well-designed prospective cohort studies to confirm whether critical illness increases the risk of subsequent osteoporosis related fractures, together with further well-designed studies to determine the factors that increase bone loss during intensive care. Clinical trials of bisphosphonates and/or vitamin D to determine the risk to benefit profile of these agents in patients with organ dysfunction are needed. However, the ready availability of these agents raises true hope that intervening in the right patients at the right time during critical illness might result in long lasting benefits to patients’ subsequent quality of life.
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